Macrophages are important for rhinovirus (RV)-induced exacerbation of asthma, but little is known about[unreadable] how macrophage activation status affects RV-intiated signaling events. Macrophage activation is a[unreadable] heterogeneous process wherein, depending on the stimuli, different classes of activated cells are generated[unreadable] that exhibit diverse immunological functions. One agent modulating macrophage function is the "classical"[unreadable] activator interferon-gamma (IFN-gamma). Conversely, alternatively-activated macrophages can be induced by IL-4[unreadable] or IL-13. These different activation states result in the liberation of distinct profiles of mediators, with[unreadable] alternatively-activated cells exhibiting a reduced antimicrobial capacity. Because IL-4/IL-13 are important in[unreadable] asthma and can also promote alternatively-activated macrophage phenotypes, and given the contribution of[unreadable] IFN-gamma to virus-induced exacerbation of asthma, we postulate that the interaction of these diverse priming[unreadable] agents leads to a range of macrophage phenotypes that affect the resolution of infection and thus airflow[unreadable] obstruction and symptoms of asthma. Our initial studies reveal that RV challenge of airway macrophages[unreadable] leads to the release of pro-inflammatory factors (TNF-alpha, IP-10, MCP-1) and that airway macrophages from[unreadable] asthmatic patients exhibit an elaboration of mediators that is characteristic of alternatively-activated cells.[unreadable] Our studies have also shown that macrophage exposure to RV activates transcription factors (NF-KB, CREB[unreadable] and STAT1) and MAP kinases (Jun kinases and p38) that regulate gene expression and cytokine production.[unreadable] The overall hypothesis of this project is that macrophages from asthmatic subjects are directed towards[unreadable] alternatively-activated phenotypes, and upon interaction with RV, release cytokines/chemokines that lead to[unreadable] asthma exacerbation. Thus, the following aims are proposed: (1) Determine whether macrophages from[unreadable] asthmatic patients are directed towards alternatively-activated phenotypes (characterized by attenuated[unreadable] release of proinflammatory cytokines (TNFalpha, IFNalpha) and chemokines (MCP-1, IP-10) but enhanced production[unreadable] of IL-10). (2) Test whether the altered cytokine responses of macrophages from asthmatic patients is[unreadable] reflected by alterations in the kinetics/ intensity of signaling via MAPK, NF-kappa, GREB and STAT1.[unreadable] (3) Ascertain whether normal human blood monocyte-derived macrophages can be directed towards[unreadable] classically-activated or alternatively-activated phenotypes by factors (IL-4, IFN-gamma) relevant to RV-induced[unreadable] exacerbation of asthma.